Nontraditional plasma markers of hyperglycemia are of increasing clinical interest in diabetes care as measures of short-term glycemic control, potential adjuncts to HbA1c, or alternatives to HbA1c when HbA1c is unreliable or impractical. However, there is little data to support their use. Aims: To compare nontraditional markers of hyperglycemia to standard measures (HbA1c and fasting glucose) to inform their value in the management of patients with type 2 diabetes. We will 1) evaluate and compare the prognostic value of nontraditional glycemic markers to standard markers as risk factors for major microvascular and macro-vascular outcomes and death; and 2) characterize their response to improved glycemic control. Design and Methods: We will measure a panel of nontraditional markers of hyperglycemia in >7,000 stored biospecimens from a completed randomized clinical trial of type 2 diabetes, the Action in Diabetes and VAscular disease: preterax and diamicroN Controlled Evaluation (ADVANCE) Trial. We will also conduct repeat measurements in a subsample of participants with blood collections at baseline and again at one year. We will complete a series of epidemiological analyses to investigate the associations of nontraditional glycemic markers with clinical outcomes during 10 years of follow-up (during the trial and extended observational follow- up) and compare these results to those observed for HbA1c and fasting glucose. We will specifically evaluate and compare the prognostic value of standard and nontraditional markers of hyperglycemia and we will characterize possible risk thresholds in the associations with microvascular and macro-vascular outcomes. We will quantify one-year change in the nontraditional markers of hyperglycemia and their change in response to tight glycemic control (trial intervention). Significance: Although it is recognized that HbA1c is a suboptimal measure of glucose control in a number of settings, data on the utility of alternative markers of hyperglycemia are scarce. This research will challenge current paradigms in clinical practice and inform whether nontraditional markers of hyperglycemia have a role alongside HbA1c and fasting glucose in clinical practice. Results of this study will have direct relevance to clinical practice and inform strategies for the management of patients with diabetes.